TWI664177B - Crystalline forms - Google Patents

Abstract

The present invention relates to (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methyl Crystal forms of oxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, preparation methods thereof, pharmaceutical compositions containing these crystal forms, and pharmaceutical combinations prepared from these crystal forms And its use as a medicament, especially as an orexin receptor antagonist.

Description

Crystal form

The present invention relates to a (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5- Novel crystalline forms of methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone (hereinafter also referred to as "compounds"), methods for their preparation, and medicines containing such crystalline forms Compositions, pharmaceutical compositions prepared from these crystalline forms and their use as orexin receptor antagonists in the treatment or prevention of sleep disorders, anxiety, addiction, cognitive dysfunction, mood disorders or appetite disorders.

Orexin (orexin A or OX-A and orexin B or OX-B) are neuropeptides discovered by two research groups in 1998, orexin A is a 33 amino acid peptide, and orexin B is a 28 amino group Acid peptides (Sakurai T et al ., Cell, 1998 , 92, 573-585). Orexin is produced in discrete neurons in the lateral hypothalamus and binds to G protein-coupled receptors (OX ₁ and OX ₂ receptors). The orexin-1 receptor (OX ₁ ) is selective for OX-A, and the orexin-2 receptor (OX ₂ ) is capable of binding OX-A and OX-B. Orexin receptor antagonists are novel neurological or psychotropic drugs. Its mode of action in animals and humans involves blocking orexin-1 and orexin-2 receptors (dual antagonists) in the brain, or individually and selectively blocking orexin-1 or orexin-2 receptors (Selective antagonist). Orexin was originally found to stimulate food consumption in rats, suggesting that these peptides act as mediators in a central feedback mechanism that regulates feeding behavior (Sakurai T. et al . Cell, 1998 , 92, 573-585).

On the other hand, orexin neuropeptides and orexin receptors play a basic and major role in regulating circadian insomnia. In the brain, orexin neurons collect sensory input about internal and external states and transmit short axonal processes and long processes to many other brain regions. The specific distribution of orexin fibers and receptors in the basal forebrain, marginal structures, and brainstem areas (areas associated with regulating wakefulness, sleep, and emotional responses) indicate that orexin performs a basic function as a behavioral arousal regulator; by activation Awakening promotes cell activation, and orexin helps arrange all brain arousal systems that regulate day and night activity, energy balance, and emotional response. This effect provides substantial treatment opportunities for medically addressing a large number of mental health conditions that may be associated with orexin-induced sexual dysfunction [see, eg, Tsujino N and Sakurai T, "Orexin / hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward systems. ", Pharmacol Rev. 2009 , 61: 162-176; and Carter ME et al.," The brain hypocretins and their receptors: mediators of allostatic arousal. ", Curr Op Pharmacol. 2009 , 9: 39- 45], which is described in the following sections. Orexin has also been observed to regulate sleep and wakefulness, providing a potentially novel treatment for insomnia and other sleep disorders (Chemelli RM et al ., Cell, 1999 , 98, 437-451).

Human memory contains multiple systems with different operating principles and different underlying neuronal matrices. The main difference is between conscious declarative memory and a group of unconscious non-declarative memory. Declarative memory is further divided into semantic memory and episodic memory. Non-declarative memory is further subdivided into priming and perceptual learning, process memory for skills and habits, joint and non-joint learning, and others. Semantic memory refers to common sense about the world, and episodic memory is autobiographical memory of events. Procedural memory refers to the ability to perform skill-based operations, such as motor skills. Beginning with learning or memory acquisition or formation, long-term memory is established in a multi-stage process through gradual changes involving different brain structures. Then, consolidating what you have learned stabilizes your memory. When retrieving long-term memory retrospectively, it may return to an unstable state where the original content can be updated, adjusted, or destroyed. Subsequently, the consolidation can be adjusted and stabilized again. In the later stages, long-term memory can be vandal-resistant. Long-term memory differs conceptually and anatomically from working memory, which is the ability to temporarily maintain a limited amount of information in the mind. Behavioral studies have shown that the human brain consolidates long-term memory at certain critical intervals. The initial stage of memory consolidation may occur in the first few minutes after we are exposed to new ideas or learning experiences. The next most important stage may occur over a longer period of time, such as during sleep; in fact, certain consolidation processes have been shown to be related to sleep [R. Stickkgold et al., Sleep-dependent memory consolidation; Nature 2005 , 437 , 1272-1278]. Xianxin learning and memory processes are fundamentally affected in a variety of neurological and mental disorders, such as mental retardation, Alzheimer's disease, or depression. In fact, memory loss or memory acquisition disorders are significant features of these diseases, and effective therapies to prevent this adverse method have not yet appeared.

In addition, anatomical and functional evidence from in vitro and in vivo studies indicates an important positive interaction between the endogenous orexin system and the brain reward pathway [Aston-Jones G et al., Brain Res 2010 , 1314, 74-90; Sharif R, et al. People, Brain Res 2010 , 1314, 130-138]. Selective pharmacological OXR-1 blockade reduces cocaine-seeking cues and stress-induced relapses [Boutrel B, et al., "Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior." Proc Natl Acad Sci 2005 , 102 (52), 19168-19173; Smith RJ et al., "Orexin / hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking." Eur J Neurosci 2009 , 30 (3), 493-503; Smith RJ et al., "Orexin / hypocretin is necessary for context-driven cocaine-seeking." Neuropharmacology 2010, 58 (1), 179-184], implied recurrence induced by alcohol seeking [Lawrence AJ et al., Br J Pharmacol 2006 , 148 (6), 752-759], and self-administration of nicotine [Hollander JA et al., Proc Natl Acad Sci 2008 , 105 (49), 19480-19485; LeSage MG et al., Psychopharmacology 2010 , 209 (2) , 203-212]. Orexin-1 receptor antagonism also weakens the expression of amphetamine and cocaine-induced CPP [Gozzi A et al., PLoS One 2011 , 6 (1), e16406; Hutcheson DM et al., Behav Pharmacol 2011 , 22 (2), 173-181], and reduce action-sensitivity manifestations or manifestations of amphetamine and cocaine [Borgland SL et al., Neuron 2006 , 49 (4), 589-601; Quarta D et al., " The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization. "Neurochem Int 2010 , 56 (1), 11-15].

Addiction-relieving effects of drugs can be mimicked in normal or particularly sensitive mammals used as animal models [see, eg, Spealman et al., Pharmacol. Biochem. Behav. 1999 , 64 , 327-336; or TS Shippenberg, GF Koob, "Recent advances in animal models of drug addiction ", Neuropsychopharmacology: The fifth generation of progress; KLDavis, D. Charney, JTDoyle, C. Nemeroff (eds.) 2002 ; Chapter 97, pp. 1381-1397].

Several pieces of converging evidence further indicate the direct role of the orexin system as a regulator of acute stress response. For example, stress (ie, psychological or physiological stress) is associated with increased arousal and insomnia, which in turn is controlled by orexin [Sutcliffe, JG et al., Nat Rev Neurosci 2002 , 3 (5), 339-349] . Orexin neurons are likely to be involved in the coordinated regulation of behavior and physiological responses in a stressful environment [Y. Kayaba et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003, 285: R581-593]. Hypothalin / orexin contributes to the expression of some but not all forms of stress and arousal [Furlong TM et al., Eur J Neurosci 2009 , 30 (8), 1603-1614]. Stress responses can cause dramatic, usually limited time, physiological, psychological, and behavioral changes that can affect appetite, metabolism, and feeding behaviors [Chrousos, GP et al., JAMA 1992 , 267 (9), 1244-1252]. Acute stress responses can include behavioral, autonomic, and endocrine changes, such as promoting insomnia strengthening, decreased libido, increased heart rate and blood pressure, or redirecting blood flow to fuel muscle, heart, and brain [Majzoub, JA et al., European Journal of Endocrinology 2006 , 155 (suppl_1) S71-S76].

As outlined above, the orexin system regulates constant functions in the body, such as sleep-wake cycles, energy balance, mood, and reward. Orexin is also involved in regulating acute behavior and autonomic nervous system response to stress [Zhang W et al., "Multiple components of the defense response depend on orexin: evidence from orexin knockout mice and orexin neuron-ablated mice." Auton Neurosci 2006 , 126 -127,139-145]. Emotional disorders, including all types of depression and bipolar disorder, are characterized by interference with "emotions" and emotions, as well as sleep problems (insomnia and excessive sleep), changes in appetite or weight and reduced pleasure, and loss of interest in daily or once-loved activities [Liu X et al., Sleep 2007 , 30 (1): 83-90]. Therefore, there is a strong rationale: Interferences in the orexin system can cause symptoms of mood disorders. For example, evidence in humans indicates that depressed patients exhibit diminished daily variation in CSF orexin content [Salomon RM et al., Biol Psychiatry 2003 , 54 (2), 96-104]. Orexin is also shown to be involved in rodent models with depression. For example, the pharmacologically induced exposure of depressive behavioral states in rats is associated with an increase in orexin content in the hypothalamus [Feng P et al., J Psychopharmacol 2008 , 22 (7): 784-791]. The chronic stress model of mouse depression also suggests that molecular orexin system interference is associated with reversal of depressive behavioral states and these molecular changes treated with antidepressants [Nollet et al., NeuroPharm 2011 , 61 (1-2): 336- 46].

The orexin system also involves stress-related appetite / reward seeking behavior (Berridge CW et al., Brain Res 2009 , 1314, 91-102). In some cases, the moderating effect on stress can be complementary to its own effect on appetite / reward seeking behavior. For example, OX ₁ selective orexin receptor antagonists can prevent recurrence induced by plantar shock pressure of cocaine seeking behavior [Boutrel, B et al., Proc Natl Acad Sci 2005 , 102 (52), 19168-19173]. In addition, it is also known that stress plays a major role in the withdrawal that occurs during cessation of drug administration (Koob, GF et al., Curr Opin Investig Drugs 2010 , 11 (1), 63-71).

Orexin has been found to increase food intake and appetite [Tsujino, N, Sakurai, T, Pharmacol Rev 2009 , 61 (2) 162-176]. As an additional environmental factor, stress can cause binge eating behavior and cause obesity [Adam, TC et al. Physiol Be hav 2007 , 91 (4) 449-458]. Animal models (as clinically relevant models of human binge eating disorder) are described, for example, in W. Foulds Mathes et al .; Appetite 2009 , 52, 545-553.

Many recent studies have reported that orexin can play a number of other important functions related to arousal, especially when the organism must respond to unexpected stressors and attacks in the environment [Tsujino N and Sakurai T. Pharmacol Rev. 2009 , 61: 162-176; Carter ME, Borg JS and deLecea L., Curr Op Pharmacol. 2009 , 9: 39-45; C Boss, C Brisbare-Roch, F Jenck, Journal of Medicinal Chemistry 2009 , 52: 891- 903]. The orexin system interacts with neural networks that regulate mood, rewards, and constant energy to maintain proper insomnia. Dysfunction in its function can therefore involve many mental health conditions, among which insomnia, arousal, awakening or disturbed attention.

Compound (2R) -2-{(1S) -6,7-dimethoxy-1- [2- (4-trifluoromethyl-phenyl) in humans when tested for indications of primary insomnia -Ethyl] -3,4-dihydro-1H-isoquinolin-2-yl} -N -methyl-2-phenyl-acetamidamine (WO2005 / 118548), a dual orexin receptor antagonist Show clinical efficacy. In rats, the compound has been shown to reduce alertness, which is characterized by reduced active arousal and exercise; and a dose-dependent increase in the time spent in REM and NREM sleep [Brisbare et al., Nature Medicine 2007 , 13 , 150-155]. This compound further attenuates the cardiovascular response to conditioned fear and novel exposure in rats [Furlong TM et al., Eur J Neurosci 2009 , 30 (8), 1603-1614]. It is also active in animal models of conditional fear: the rat fear-enhancing paradigm paradigm (WO2009 / 047723), which involves emotional states of fear and anxiety disorders such as anxiety including phobia and post-traumatic stress disorder (PTSD) . In addition, full declarative and non-declarative learning and memory have been demonstrated in rats treated with this compound [WO2007 / 105177, H Dietrich, F Jenck, Psychopharmacology 2010 , 212, 145-154]. The compound further reduces the brain content of amyloid-beta (Aβ) and Aβ plaque deposition after acute sleep restriction in amyloid precursor protein transgenic mice [JE Kang et al., "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. ", Science 2009 , 326 (5955): 1005-1007]. It is assumed that the accumulation of Aβ in the extracellular space of the brain is an important event in the pathogenesis of Alzheimer's disease. The so-called and commonly known "amyloid cascade hypothesis" correlates Aβ with Alzheimer's disease and therefore with cognitive dysfunction expressed as learning and memory disorders. This compound has also been shown to induce antidepressant-like activity upon long-term administration in a mouse model of depression [Nollet et al., NeuroPharm 2011 , 61 (1-2): 336-46]. In addition, this compound has been shown to attenuate orexin A-induced natural activity in fasted hungry rats exposed to food odors [MJ Prud'homme et al., Neuroscience 2009 , 162 (4), 1287-1298]. This compound also shows pharmacological activity in a rat model of nicotine self-administration [LeSage MG et al., Psychopharmacology 2010 , 209 (2), 203-212]. Another dual orexin receptor antagonist, N-bibiphenyl-2-yl-1-{[((1-methyl-1H-benzimidazol-2-yl) thio] ethyl}}-L- Proline amine inhibits the recurrence of nicotine in conditional enhancers and reduces behavior (action sensitization) and molecular (transcriptional response) changes induced by repeated amphetamine administration in rodents [Winrow et al., Neuropharmacology 2009 , 58 (1), 185-94].

Orexin receptor antagonists comprising 2-substituted saturated cycloamidine derivatives, such as 2-substituted pyrrolidine-1-carboxamide, are known, for example, from the following: WO2008 / 020405, WO2008 / 038251, WO2008 / 081399, WO2008 / 087611, WO2008 / 117241, WO2008 / 139416, WO2009 / 004584, WO2009 / 016560, WO2009 / 016564, WO2009 / 040730, WO2009 / 104155, WO2010 / 004507, WO2010 / 038200, WO2001 / 096302, WO2002 / 044172, WO2002 / 089800 , WO2002 / 090355, WO2003 / 002559, WO2003 / 032991, WO2003 / 041711, WO2003 / 051368, WO2003 / 051873, WO2004 / 026866, WO2004 / 041791, WO2004 / 041807, WO2004 / 041816, WO2009 / 003993, WO2009 / 003997, WO2009 / 124956, WO2010 / 060470, WO2010 / 060471, WO2010 / 060472, WO2010 / 063662, WO2010 / 063663, WO2010 / 072722, WO2010 / 122151, and WO2008 / 150364. Specific pyrrolidine-derived compounds with high orexin-1 selectivity are disclosed in Langmead et al., Brit. J. Pharmacol. 2004 , 141, 340-346. WO2003 / 002561 discloses certain N-arylfluorenyl cyclic amine derivatives (including pyrrolidine derivatives substituted with benzimidazol-2-yl-methyl) as an orexin receptor antagonist. Despite a large number of prior art compounds and their high structural changes, all compounds share common structural features, i.e., a linking group such as at least one methylene group (or such as -CH ₂ -NH-CO -, -CH ₂ -NH-, -CH ₂ -O-, -CH ₂ -S- and other longer groups) linking group to link the cyclofluorenylamine to the corresponding aromatic ring system substituent. Despite the expected substantial conformational change in the presence of a linker that can be self-removed between two rigid structural members, the compound of the present crystalline form (having a benzimidazole ring directly attached to pyrrolidinamide at position 2) is orexin Dual antagonists of the 1 receptor and the orexin 2 receptor, and therefore in the treatment of orexin-induced disorders (especially including sleep disorders, anxiety, addiction, cognitive dysfunction, mood disorders or appetite disorders) ), And has potential use, especially in the treatment of sleep disorders, anxiety and addiction.

It has now been found that certain crystalline forms of a compound can be obtained under certain conditions. Given the potential use of the compound as an active pharmaceutical ingredient, these crystalline forms of the compound are novel and may have advantageous properties. These advantages may include better flow characteristics; poorer hygroscopicity; better manufacturing reproducibility (such as better filtration parameters, better formation reproducibility, and / or better sedimentation); and / or prescribed morphology. These crystalline forms of the compounds may be particularly useful in methods of making certain pharmaceutical compositions, especially lipid-based pharmaceutical compositions.

FIG. 1 shows an X-ray powder diffraction pattern of the compound in an amorphous form as obtained from Reference Example 1. FIG. The X-ray diffraction pattern shows an amorphous substance.

Figure 2 shows an X-ray powder diffraction pattern of the compound in Form 1 as obtained from Example 1. X Ray diffraction patterns show peaks with relative intensity (relative peak intensity shown in parentheses) at the specified refraction angle 2θ as compared to the densest peaks in the graph (reported 2θ ranges from 3 ° to 40 ° with relative intensity greater than 10) % Of selected peaks): 8.6 ° (84%), 11.5 ° (45%), 13.4 ° (44%), 14.6 ° (43%), 15.2 ° (100%), 15.5 ° (72%), 17.1 ° (36%), 18.4 ° (22%), 19.3 ° (42%), 19.8 ° (27%), 21.3 ° (62%), 21.9 ° (14%), 22.4 ° (36%), 23.1 ° (13%), 23.5 ° (25%), 25.7 ° (27%), 26.4 ° (36%), 26.8 ° (22%), 27.9 ° (22%), and 29.7 ° (17%)

Figure 3 shows an X-ray powder diffraction pattern of the compound in Form 2 as obtained from Example 2. The X-ray diffraction pattern measured with Method 2 shows a peak having a relative intensity at a specified refraction angle 2θ at the specified refraction angle 2θ (relative peak intensity is shown in parentheses) compared to the densest peak in the graph (reported 2θ range is 3 ° to 40 °, selected peak with relative intensity greater than 10%): 7.2 ° (38%), 10.9 ° (69%), 13.4 ° (83%), 14.3 ° (70%), 14.5 ° (70%), 14.9 ° (71%), 16.1 ° (14%), 17.2 ° (47%), 18.3 ° (82%), 19.8 ° (14%), 20.0 ° (11%), 20.6 ° (15%), 20.9 ° (85%), 21.1 ° (100%), 21.8 ° (44%), 22.3 ° (14%), 22.9 ° (27%), 24.0 ° (71%), 27.7 ° (13%), 25.0 ° ( 17%), 25.2 ° (30%), 27.0 ° (16%), 27.3 ° (32%), 28.9 ° (13%), 30.1 ° (45%), 30.4 ° (13%), 32.7 ° (11 %) And 36.0 ° (16%)

To avoid any doubt, the peaks listed above describe the experimental results of X-ray powder diffraction shown in Figures 2 and 3 respectively. It should be understood that, compared to the list of peaks above, only the characteristic peaks need to be selected to adequately and unambiguously characterize the compounds of the present invention in corresponding crystal forms.

In the X-ray diffraction charts of FIGS. 1 to 3, the refraction angle 2θ is plotted on the horizontal axis, and the count is plotted on the vertical axis.

FIG. 4 shows a gravity vapor adsorption diagram of a compound in the form of an amorphous free base as obtained from Reference Example 1. FIG.

FIG. 5 shows a gravity vapor adsorption diagram of the compound in Form 1 as obtained from Example 1. FIG.

Figure 6 shows a gravity vapor adsorption diagram of the compound in Form 2 as obtained from Example 2.

In the gravity vapor adsorption diagrams of FIGS. 4 and 6, the relative humidity (RH%) is plotted on the horizontal axis, and the mass change (dm%) is plotted on the vertical axis.

1) The first embodiment of the present invention relates to compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidine- Crystalline form of 1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone; its characteristics are: a) in the X-ray powder diffraction pattern The following peaks of the refraction angle 2θ are present in: 8.6 °, 15.2 °, and 21.3 °; or b) The following peaks of the refraction angle 2θ are present in the X-ray powder diffraction pattern: 13.4 °, 18.3 °, and 24.0 °.

It should be understood that the crystalline form according to Example 1) includes a compound in the crystalline form of the free base (ie not in the form of a salt). In addition, the crystalline forms may include non-coordinating and / or coordinating solvents. Coordination solvents are used herein as a term for crystalline solvates. Similarly, non-coordinating solvents are used herein as terms for physical adsorption or physical coating solvents (according to Polymorphism in the Pharmaceutical Industry (Ed.R. Hilfiker, VCH, 2006), Chapter 8: UJGriesser: The Importance of Solvates )). Form 1 is especially hemihydrate, ie it contains about 0.5 equivalents of coordination water, and may contain additional non-coordination solvents, such as isopropanol, ethanol and / or water, especially water. Form 2 does not particularly include complexing water, but may include non-complexing solvents such as isopropanol, ethanol, and / or water.

2) Another embodiment relates to a crystalline form of the compound according to Example 1), which is characterized in that the following peaks of the refraction angle 2θ exist in the X-ray powder diffraction pattern: 8.6 °, 15.2 °, and 21.3 °.

3) Another embodiment relates to the crystalline form of a compound according to Example 1), which is characterized by the presence of the following peaks of refraction angle 2θ in the X-ray powder diffraction pattern: 8.6 °, 15.2 °, and 21.3 °; or The crystal form according to embodiment 2) is characterized in that the following peaks of the refraction angle 2θ exist in the X-ray powder diffraction pattern: 8.6 °, 11.5 °, 13.4 °, 14.6 °, 15.2 °, 15.5 °, 19.3 °, 21.3 °, 22.4 ° and 26.4 °.

4) Another embodiment relates to the crystalline form of a compound according to Example 1), which is characterized by the presence of the following peaks of the refraction angle 2θ in the X-ray powder diffraction pattern: 8.6 °, 15.2 °, and 21.3 °; or According to the crystalline form of embodiment 2) or 3), it basically shows an X-ray powder diffraction pattern as depicted in FIG. 2.

5) Another embodiment relates to the crystalline form of a compound according to Example 1), which is characterized in that the following peaks of the refraction angle 2θ exist in the X-ray powder diffraction pattern: 8.6 °, 15.2 °, and 21.3 °; or The crystal form of any of Examples 2) to 4), as measured by differential scanning calorimetry using the method described herein, has a broad peak endothermic event in the range of about 50 ° C to 160 ° C.

6) In another embodiment, the present invention relates to a crystalline form of the compound according to Embodiment 1), which is characterized in that the following peaks of the refraction angle 2θ exist in the X-ray powder diffraction pattern: 8.6 °, 15.2 °, and 21.3 ° Or regarding the crystalline form according to any one of embodiments 2) to 5), wherein the form is obtainable by: a) mixing 2 g of an amorphous substance compound with 8 mL of a volume / volume ratio of 1/4 ethanol / water The mixture; b) adding about 0.05 g of a seed crystal of the compound in crystalline form 1 (e.g., obtainable using the procedure of Example 1 below); c) shaking at 300 rpm at room temperature for about 16 hours; d) filtering and using 2 mL of ethanol / water 1 / 4 (v / v) The filter cake was washed, and the product was dried under reduced pressure at room temperature and about 10 mbar for 4 hours; and e) opened for equilibrium for 2 hours at room temperature and about 60% relative humidity.

7) Another embodiment relates to the crystalline form of a compound according to Example 1), which is characterized in that the following peaks of the refraction angle 2θ exist in the X-ray powder diffraction pattern: 8.6 °, 15.2 °, and 21.3 °; or The crystalline form of any one of Examples 2) to 6), wherein the crystalline form is a hemihydrate (that is, each equivalent compound contains about 0.5 equivalent of coordination water; it should be understood that about 0.5 equivalent Coordinated water corresponds to a crystalline form having a water content of about 1.96%).

8) Another embodiment relates to a crystalline form of the compound according to Example 1, which is characterized in that the following peaks of the refraction angle 2θ exist in the X-ray powder diffraction pattern: 13.4 °, 18.3 °, and 24.0 °.

9) Another embodiment relates to a crystalline form of the compound according to Example 1), which is characterized in that the following peaks of the refraction angle 2θ exist in the X-ray powder diffraction pattern: 13.4 °, 18.3 °, and 24.0 °; or The crystal form of Example 8) is characterized in that the following peaks of refraction angle 2θ exist in the X-ray powder diffraction pattern: 10.9 °, 13.4 °, 14.3 °, 14.9 °, 18.3 °, 20.9 °, 21.1 °, 21.8 °, 24.0 ° And 30.1 °.

10) Another embodiment relates to the crystal form of a compound according to Example 1), which is characterized by the presence of the following peaks of refraction angle 2θ in the X-ray powder diffraction pattern: 13.4 °, 18.3 °, and 24.0 °; or According to the crystal form of embodiment 8) or 9), it basically shows an X-ray powder diffraction pattern as depicted in FIG. 3.

11) Another embodiment relates to the crystal form of a compound according to Example 1), which is characterized by the presence of the following peaks of refraction angle 2θ in the X-ray powder diffraction pattern: 13.4 °, 18.3 °, and 24.0 °; or According to the crystal form of any one of Examples 8) to 10), its melting point is about 152 ° C, as determined by differential scanning calorimetry (using the method as described herein).

12) In another embodiment, the present invention relates to a crystalline form of the compound according to Example 1), which is characterized by the following peaks of the refraction angle 2θ in the X-ray powder diffraction pattern: 13.4 °, 18.3 °, and 24.0 °; or regarding the crystal form according to any one of embodiments 8) to 11), wherein the form is obtained by: a) mixing 10 mg of the compound in crystal form 1 in 0.05 mL of acetonitrile; b) in a closed 4 mL vial Stir for up to three days; c) separate; and dry under reduced pressure (2 mbar) and room temperature for 2 hours.

13) Another embodiment relates to the crystalline form of a compound according to Example 1), which is characterized by the presence of the following peaks of refraction angle 2θ in the X-ray powder diffraction pattern: 13.4 °, 18.3 °, and 24.0 °; or regarding the crystalline form according to any one of embodiments 8) to 12), wherein the crystalline form is an anhydrate (that is, it does not contain coordination water).

To avoid any doubt, as long as one of the above examples mentions the "peak of the following refraction angle 2θ in the X-ray powder diffraction pattern", the X-ray powder diffraction pattern is radiated by using a combination of Cu Kα1 and Kα2 (Without Kα2 stripping) obtained; and it should be understood that the accuracy of the 2θ values provided herein is in the range of +/- 0.1 ° to 0.2 °. It is worth noting that when the refraction angle 2θ of the peak is specified in the embodiment of the present invention and the scope of the patent application, the given 2θ is understood as the interval between the value minus 0.2 ° and the value plus 0.2 ° (2θ +/- 0.2 °); Preferably, the value is reduced by 0.1 ° to the value plus 0.1 ° (2θ +/- 0.1 °).

When plural forms are used for compounds, solids, pharmaceutical compositions, diseases, and the like, this is also meant to mean a single compound, solid, or the like.

The term "enantiomeric enrichment" is understood in the context of the present invention to mean, in particular, at least 90% by weight, preferably at least 95% by weight, and most preferably at least 99% by weight of the compound exists as an enantiomer of the compound. It is understood that the compounds exist in an absolute (S) -configuration with enantiomeric enrichment.

The term "substantially pure" is understood in the context of the present invention to mean, in particular, at least 90 wt%, preferably at least 95 wt%, and most preferably at least 99 wt% of the crystals of the compound are present in the crystal formation according to the present invention, especially as the A single crystal was formed.

When a definition peak exists in, for example, an X-ray powder diffraction pattern, a common method makes this definition in terms of an S / N ratio (S = signal, N = noise). According to this definition, when the stated peak must exist in the X-ray powder diffraction pattern, it should be understood that the peaks in the X-ray powder diffraction pattern are by having a value greater than x (x value greater than 1), usually greater than 2, especially greater than 3. S / N ratio (S = signal, N = noise) is defined.

In the case where the stated crystal form basically shows the X-ray powder diffraction patterns as depicted in Figures 2 or 3 respectively, the term "substantially" means at least the major peaks of the patterns depicted in those figures (i.e. Relative intensity of the densest peaks in the diagram is greater than 10%, especially greater than 20% (Peak) must exist. However, those skilled in X-ray powder diffraction will recognize that the relative intensity in the X-ray powder diffraction pattern can withstand strong intensity changes due to better orientation effects.

Unless used with regard to temperature, the term "about" before the value "X" in this application refers to an interval of X minus 10% X extending to X plus 10% X, and preferably X minus 5% X extending to X plus 5% X. Under certain temperature conditions, the term "about" before the temperature "Y" refers to the interval between the temperature Y minus 10 ° C and Y plus 10 ° C, preferably Y minus 5 ° C to Y plus 5 ° C. The interval, in particular, extends from Y minus 3 ° C to Y plus 3 ° C. Room temperature means a temperature of about 25 ° C. When the term n equivalent (where n is a number) is used in this application, this means and within the scope of this application: n refers to the approximate number n, preferably n refers to the exact number n.

Whenever the words "between" or "to" are used to describe a numerical range, it should be understood that the endpoints of the specified range are explicitly included in the range. For example: if the temperature range is described as between 40 ° C and 80 ° C (or 40 ° C to 80 ° C), this means that the endpoints of 40 ° C and 80 ° C are included in the range; or if the variables are defined as 1 and 4 (Or 1 to 4), this means that the variable is an integer 1, 2, 3, or 4.

The expression% w / w refers to the weight percentage compared to the total weight of the composition under consideration. Similarly, the expression v / v refers to the volume ratio of the two components under consideration. The expression "vol" means a volume (L, such as a solvent) per weight (kg, such as a reactant). For example, 7vol means 7 liters (solvent) per kg (reactant).

The crystalline form, especially substantially pure crystalline form, of the compound according to any one of embodiments 1) to 13) can be used as a medicament, for example in the form of a pharmaceutical composition for enteral or parenteral administration.

12) Therefore, another embodiment relates to a compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazole) according to any one of Examples 1) to 13). -2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, It is used as a medicament.

A crystalline solid, in particular a substantially pure crystalline solid, of the compound according to any one of embodiments 1) to 13) can be used as a single component or as a compound with other crystalline or amorphous forms of the compound mixture.

The manufacture of pharmaceutical compositions can be accomplished in any manner familiar to those skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy , 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [by Lippincott Williams & Wilkins Published]), by combining the crystalline form of the present invention (as appropriate with other therapeutically valuable substances) and suitable non-toxic, inert, pharmaceutically acceptable solid or liquid carrier substances and (if necessary) common A pharmaceutical adjuvant is introduced into the galen dosage form.

14) Another embodiment of the present invention pertains to the compound (S)-(2- (6-chloro-7-methyl-1H-benzene) according to any one of Examples 1) to 13) as an active ingredient. ([D] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) A crystalline pharmaceutical composition of ketone and at least one pharmaceutically acceptable carrier substance.

These pharmaceutical compositions according to Example 14) are particularly suitable for the prevention or treatment of diseases or disorders related to the orexin system, such as in particular sleep disorders, anxiety, addiction, cognitive dysfunction, mood disorders or appetite disorders.

15) Another embodiment of the present invention relates to a pharmaceutical composition according to embodiment 14), wherein the pharmaceutical composition is in the form of a lozenge.

16) Another embodiment of the present invention relates to a pharmaceutical composition according to embodiment 14), wherein the pharmaceutical composition is in the form of a capsule.

17) Another embodiment of the present invention relates to a compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d]) according to any one of Examples 1) to 13). Crystalline form of imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone [Especially according to the crystalline form of any one of embodiments 2) to 7)], which is used for manufacturing a pharmaceutical composition, which contains the compound (S)-(2- (6-chloro-7) as an active ingredient -Methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazole- 2-yl) phenyl) methanone, and at least one pharmaceutically acceptable carrier substance.

In order to avoid any doubt, Example 17) refers to the method according to any one of Examples 1) to 13). Crystal form [especially the crystal form according to any one of embodiments 2) to 7)] which is suitable for / used as a final separation step of a compound (for example, in order to meet the purity requirements of pharmaceutical manufacturing), and a final medicine according to embodiment 17) The composition may or may not contain the crystalline form (e.g., because the initial crystalline form of the compound is further transformed during the manufacturing process and / or dissolved in a pharmaceutically acceptable carrier substance; therefore, in the final pharmaceutical composition, the compound may be non- Crystalline form, in another crystalline form, or in dissolved form or a similar form).

18) Therefore, another embodiment of the present invention relates to the compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl)- 2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, wherein the pharmaceutical combination The compound uses the compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2- according to any one of Examples 1) to 13). Methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone crystalline forms [especially according to Example 2) to 7 ), And at least one pharmaceutically acceptable carrier substance.

19) Another embodiment of the present invention relates to a pharmaceutical composition according to embodiment 18), wherein the pharmaceutical composition is in the form of a capsule.

20) Another embodiment of the present invention relates to a pharmaceutical composition according to embodiment 18) or 19), wherein the pharmaceutical composition is a lipid-based formulation (see, for example, CWPouton, CJHPorter, Advanced Drug Delivery Reviews 60 (2008) 625-637, the disclosure of which is fully incorporated herein).

21) Another embodiment of the present invention relates to a pharmaceutical composition according to Embodiment 18), wherein the pharmaceutical composition is a solid amorphous dispersion.

22) Another embodiment of the present invention relates to a pharmaceutical composition according to embodiment 21), wherein the pharmaceutical composition is in the form of a tablet or in the form of a capsule.

The pharmaceutical compositions according to Examples 18) to 22) are particularly suitable for preventing or treating diseases or conditions related to the orexin system, such as sleep disorders, anxiety, addiction, cognitive dysfunction, mood disorders, or appetite disorders ); Especially suitable for prevention or treatment where The above diseases or conditions (especially sleep disorders or anxiety disorders) that require a shorter onset of action.

23) Another embodiment of the present invention relates to a compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d]) according to any one of Examples 1) to 13). Crystalline form of imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone It is used to prevent or treat diseases or conditions related to the orexin system, especially mental health diseases or conditions related to orexin dysfunction.

24) Another embodiment of the present invention relates to the compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazole) according to any one of embodiments 1) to 13). -2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, It is used for the preparation of a medicament for preventing or treating a disease or condition related to the orexin system, particularly a mental health disease or condition related to orexin dysfunction.

25) Another embodiment of the present invention relates to the pharmaceutical composition according to any one of embodiments 14) to 16) or 18) to 22) for preventing or treating a disease or disorder related to the orexin system, Mental health diseases or disorders particularly related to orexinergic dysfunction.

26) Another embodiment of the present invention relates to any one of embodiments 23) to 25), wherein the diseases or conditions related to the orexin system are mental health diseases or conditions related to orexin dysfunction These mental health diseases or disorders are selected from the group consisting of sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunction, mood disorders and appetite disorders (especially sleep disorders, anxiety disorders and addiction disorders).

25) Another embodiment of the present invention is related to any one of embodiments 22) to 25), wherein the diseases or conditions related to the orexin system are orexinergic dysfunctions selected from the group consisting of Associated mental health disease or disorder: Sleep disorder, selected from the group consisting of dyssomnias, sleep-like disorders, sleep disorders related to general medical conditions and substance-induced sleep disorders; anxiety disorders; and addiction.

These disorders associated with orexin dysfunction are diseases or disorders in which an antagonist of the human orexin receptor is required, and in particular mental health associated with orexin dysfunction Illness. In particular, the above-mentioned conditions can be defined as including sleep disorders, anxiety, addiction, cognitive dysfunction, mood disorders, or appetite disorders. In a sub-embodiment, the aforementioned conditions include, in particular, anxiety, addiction, and mood disorders, particularly anxiety and addiction. In another sub-embodiment, the aforementioned conditions include, inter alia, sleep disorders.

In addition, other disorders related to orexinergic dysfunction are selected from the group consisting of treating, controlling, improving, or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuralgia; and treating or controlling Parkinson's disease); treatment or control of psychosis including acute mania and bipolar disorder; treatment or control of stroke, especially ischemic or hemorrhagic stroke; blocking emetic response, i.e. nausea and vomiting; and treatment or control alone or with another Medical conditions complicated by agitation.

The distinction between anxiety disorders can be the main goal or specificity of the threat, and can range from generalized anxiety disorders to those limited to those encountered in fear anxiety (PHOB) or post-traumatic stress disorder (PTSD). Therefore, anxiety disorder can be defined as including generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), panic anxiety disorder (PAD) including panic attacks, fear anxiety disorder ( (PHOB), specific phobia, social phobia (social anxiety), avoidance, somatization disorders including suspected disorders, separation anxiety, anxiety due to general medical conditions, and substance-induced anxiety. In a sub-embodiment, specific examples of localized threat-induced anxiety are fear anxiety or post-traumatic stress disorder. Anxiety disorders include, in particular, post-traumatic stress disorder, obsessive-compulsive disorder, panic attacks, fear anxiety, and avoidance.

Addiction can be defined as an addiction to one or more reward stimuli, particularly one reward stimulus. These incentives can be of natural or synthetic origin. Examples of such incentives are substances / drugs {substances / drugs of natural or synthetic origin; such as cocaine, amphetamines, opiates [natural or (semi) synthetic opiates such as morphine or heroin (heroin)], cannabis, alcohol, mescalline, nicotine and the like}, the substances / drugs can be consumed alone or in combination; or other incentives to stimulate {natural sources (such as food (Such as gambling or Internet / IT (such as excessive gaming or inappropriate participation in online social network connection sites or blogging)) And other analogous incentives]}. In a sub-embodiment, addictions related to mental substance use, abuse, seeking and recurrence are defined as all types of psychological or physical and their associated allowable addictions and related components. Substance-related addiction disorders include, inter alia, substance use disorders such as substance dependence, substance craving, and substance abuse; substance-induced disorders such as substance poisoning, substance withdrawal, and substance-induced delirium. The expression "preventing or treating addiction" (that is, preventive or curative treatment of patients who have been diagnosed with or at risk of developing addiction) refers to reducing addiction, particularly reducing the onset of addiction to weaken its maintenance, promote Withdrawal, promote abstinence or remission, reduce or prevent recurrence of addiction (especially reduce the incidence of addiction, promote withdrawal or remission, reduce or prevent recurrence of addiction).

Emotional disorders include major depressive episodes, manic episodes, mixed episodes, and mild manic episodes; depression includes major depression, mood disorders; bipolar disorder includes bipolar disorder type I, bipolar disorder type II (recurrent major depressive episode Concurrent mild manic episodes), circulatory affective mental disorders; emotional disorders, including subtypes attributed to general medical conditions (including concurrent depressive features, concurrent major depressive episodes, concurrent manic features, and mixed mixed features) Emotional disorders, material-induced emotional disorders (including the subtypes of concurrent depression, manic and mixed characteristics). These mood disorders are especially severe depressive episodes; major depression; mood disorders due to general medical conditions; and substance-induced mood disorders.

Anorexia includes eating disorders and drinking disorders. Eating disorders can be defined as including eating disorders associated with excessive food intake and related complications; anorexia; forced eating disorders; obesity (attributable to any cause, regardless of genetic or environmental reasons); obesity-related disorders, including diet Obesity observed in patients with overdose and type 2 (non-insulin-dependent) diabetes; bulimia, including bulimia nervosa; malignant constitution; and bulimia. Specific eating disorders Disorders include metabolic dysfunction; anorexia: forced obesity; bulimia or anorexia nervosa. In a sub-embodiment, eating disorders may be defined to include, in particular, anorexia nervosa, bulimia, cachexia, bulimia, or obesity. Drinking disorders include thirst in mental disorders and all other types of excess fluid intake. Pathologically altered food intake can be caused by disturbed appetite (attracted to or rejected by food); altered energy balance (intake versus consumption); disturbed perception of food quality (high fat or carbohydrate, high palatability) ; Disturbed food availability (unrestricted diet or lack) or disrupted water balance.

Cognitive dysfunction includes transient or long-term appearance in mental, neurological, neurodegenerative, cardiovascular, and immune disorders, and transient or long-term attention, learning, and especially in the normal, healthy, young, adult, or especially elderly Insufficient memory function. Cognitive dysfunction relates in particular to the enhancement or maintenance of memory in patients who have been diagnosed with or at risk of developing a disease or disorder, in which memory (especially declarative or programmed memory) is reduced to symptoms [ Specific dementias, such as frontotemporal dementia or dementia with Lewy body or (especially) Alzheimer's disease]. In particular, the term "prevention or treatment of cognitive dysfunction" relates to the clinical manifestations (in particular, Manifested as declarative insufficiency), in patients with enhanced or maintained memory. In addition, the term "preventing or treating cognitive dysfunction" also relates to improving memory consolidation in any of the above patient groups.

Sleep disorders include sleep disorders, sleep-like disorders, sleep disorders related to general medical conditions, and substance-induced sleep disorders. In particular, sleep disorders include endogenous sleep disorders (especially insomnia, respiratory-related sleep disorders, periodic limb movement disorders, and restless legs syndrome), exogenous sleep disorders, and circadian sleep disorders. Sleep disorders include, in particular, insomnia, primary insomnia, idiopathic insomnia, insomnia related to depression, emotional / emotional disorders, aging, Alzheimer's disease or cognitive impairment; REM sleep disturbances; respiratory-related sleep disorders; sleep breathing Pause; periodic limb movement disorders (nocturnal myoclonus), restless legs Group, circadian rhythm sleep disorder; shift work sleep disorder; timely poor syndrome. Sleep-like disorders include arousal disorders and sleep-wake transition disorders; sleep-like disorders include, in particular, nightmares, sleep panic disorder, and sleepwalking. Sleep disorders associated with general medical conditions are, in particular, sleep disorders associated with diseases such as mental disorders, neurological disorders, neuralgia, and heart and lung diseases. Substance-induced sleep disorders include, in particular, the following subtypes: insomnia type, sleep-like type, and mixed type, and specifically include conditions due to drug-induced reduction in REM sleep as a side effect. Sleep disorders include, in particular, all types of insomnia, sleep-related dystonia; restless legs syndrome; sleep apnea; jet lag syndrome; shift sleep disorders, delayed or advanced sleep periods or insomnia related to mental disorders. In addition, sleep disorders further include aging-related sleep disorders; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; sadness; pain or illness.

In the present invention, it should be understood that if certain environmental conditions, such as stress or fear (where stress may be a social source (e.g., social stress) or a physiological source (e.g., physiological stress), including stress caused by fear), promote or facilitate previous In any of the defined conditions or diseases, the compounds of the present invention are particularly useful for treating such environmental condition conditions or diseases.

The present invention also relates to a method for preventing or treating the diseases or conditions mentioned herein, comprising administering to a subject a pharmaceutically active amount of a compound (S)-(2) according to any one of embodiments 1) to 13). -(6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1, A crystalline form of 2,3-triazol-2-yl) phenyl) methanone, or a pharmaceutical composition according to any one of Examples 14) to 16) or 18) to 20).

The present invention also relates to a method for preparing a compound in an enantiomerically enriched form, and for preparing and characterizing a compound (S)-(2-) according to any one of the examples 1) to 13). (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2 , 3-Triazol-2-yl) phenyl) methanone. These methods are described in Examples 6) and 12) and the procedures in the experimental section below.

Experimental procedure: Abbreviations (as used above or below):

Ac ethanoyl (such as in OAc = acetate, AcOH = acetic acid)

AcOH

anh. anhydrous

aq. aqueous solution

atm

tBME tertiary butyl methyl ether

Boc third butoxycarbonyl

Boc ₂ O di-tert-butyl dicarbonate

BSA bovine serum albumin

Bu butyl, such as in tBu = tert-butyl / tertiary butyl

CC silica column chromatography

CHO Chinese Hamster Ovary

conc.

DCE 1,2-dichloroethane

DCM dichloromethane

DEA Diethylamine

DIPEA diisopropylethylamine

DMF N, N -dimethylformamide

DMSO

EDC

ELSD evaporative light scattering detection

eq equivalent

ES Electronic Spray

Et ethyl

Et ₂ O ether

EtOAc ethyl acetate

EtOH ethanol

Ex. Examples

FC Silicone Flash Chromatography

FCS fetal bovine serum

Fig

FLIPR fluorescent imaging plate reader

h hours

HATU 1- [bis (dimethylamino) methylene] -1 H -1,2,3-triazolo [4,5- b ] pyridine 3-oxohexafluorophosphate

HBSS Hank's balanced salt solution

HBTU N, N, N'N' -tetramethyl- O- (1H-benzotriazol-1-yl) Hexafluorophosphate

HEPES 4- (2-hydroxyethyl) -piperazine-1-ethanesulfonic acid

¹ H-NMR proton nuclear magnetic resonance

HPLC

LC-MS liquid chromatography mass spectrometry

Lit. Literature

M accurate mass (e.g. for LC-MS)

Me methyl

MeCN Acetonitrile

MeOH methanol

MeI methyl iodide

MHz Megahertz

μl microliter

min minutes

MS Mass Spectrometry

N Normal

Pd (OAc) ₂ palladium diacetate

Pd (PPh ₃ ) ₄ (triphenylphosphine) palladium (0)

PL-HCO ₃ polymer-based bicarbonate

Ph phenyl

PPh ₃ Triphenylphosphine

prep.

RT room temperature

sat. saturated

TBTU O- (benzotriazol-1-yl) -N, N, N ', N'-tetrafluoroborate tetramethyl

TEA Triethylamine

TFA trifluoroacetic acid

Tf trifluoromethanesulfonyl

THF tetrahydrofuran

t _R residence time

UV

I-chemicals

All temperatures are stated in ° C. Commercially available starting materials were used as such without further purification. Compounds were purified by silica gel flash column chromatography (FC) or by preparative HPLC. The compounds described in the present invention are characterized by LC-MS (retention time t _{R is} given in min; molecular weight obtained from mass spectrometry is given in g / mol, using the conditions listed below). If the mass is undetectable, the compound is also characterized by ¹ H-NMR (400 MHz: Bruker; chemical shifts are given in ppm relative to the solvent used; multimodality: s = single peak, d = doublet, t = Triplet; p = quintet, hex = hexaplex, hept = sevenfold, m = multiple peak, br = wide peak, coupling constant given in Hz).

Preparative HPLC for purification of compounds (Condition C)

Tubular column: Waters XBridge (10 μm, 75 × 30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH ₄ OH (25% aq.) [Eluent B]; gradient: 90% B → 5% B after 6.5 min. (Flow rate: 75 ml / min). Detection: UV + ELSD.

Preparative HPLC for purification of compounds (Condition D)

Column: Waters Atlantis T3 OBD (10 μm, 75 × 30 mm). Conditions: MeCN [Dissociator A]; Water + 0.5% HCOOH [Dissociator B]; Gradient: 90% B → 5% B after 6.4 min. (Flow rate: 75 ml / min). Detection: UV + ELSD.

LC-MS under acidic conditions

Device: Agilent 1100 series (MS: Finnigan single quadrupole) with mass spectrometry detection. Column: Agilent Zorbax SB-Aq, (3.5 μm, 4.6 × 50 mm). Conditions: MeCN [Dissociating Agent A]; Water + 0.04% TFA [Dissociating Agent B]. Gradient: 95% B → 5% B over 1.5 min. (Flow rate: 4.5 ml / min). Detection: UV + MS.

X-ray powder diffraction (XRPD) analysis

X-ray powder diffraction patterns (coupling 2θ / θ) were collected on a Bruker D8 Advance X-ray diffractometer with a Lynxeye detector operating in a reflective manner under CuK _a -radiation. Generally, X-ray tubes are operated at 40kV / 40 mA. Apply a step size of 0.02 ° (2θ) and a step time of 76.8 seconds in a 2θ scan range of 3 ° to 50 °. Set the divergence slit to a fixed value of 0.3. The powder was pressed slightly into the silicon single crystal sample holder at a depth of 0.5 mm, and the sample was rotated in its own plane during the measurement. Diffraction data were reported using a combination of Cu Kα1 and Kα2 radiation (without Kα2 stripping). As provided herein, the accuracy of the 2θ value is in the range of +/- 0.1 ° to 0.2 °, which is generally the same as the X-ray powder diffraction pattern recorded conventionally.

Gravity vapor adsorption (GVS) analysis

The measurement of the compound amorphous free base and the compound crystal form 1 and crystal form 2 was performed simultaneously on a multi-sample instrument SPS-100n (Projekt Messtechnik, Ulm, Germany) operating in step mode at 25 ° C. Before starting the predefined humidity program (40-0-95-0-95-40% RH, 5% △ RH steps), equilibrate the samples at 40% RH, and apply the maximum of 24 hours in each step Great equilibrium time. Approximately 20 mg to 30 mg of each sample was used. Hygroscopic classification according to the European Pharmacopeia Technical Guide (1999, p. 86), for example, slightly hygroscopic: mass increase less than 2 mass% and equal to or greater than 0.2 mass%; hygroscopicity: mass increase less than 15 mass% and equal to or greater 2% by mass. Consider first the mass change between 40% relative humidity and 80% relative humidity in the adsorption scan.

Differential scanning calorimetry (DSC)

The DSC data was collected on a Mettler Toledo STARe System (DSC822e module with a ceramic sensor and a 9.20 version of the STAR software measurement unit) equipped with a 34-position self-sampler using the energy and temperature of an indium-calibrated instrument identified. Unless otherwise stated, 1 mg to 5 mg grams of each sample are usually heated from -20 ° C to 280 ° C at 10 ° C min ^-1 in an automatic piercing aluminum pan. Maintain a nitrogen flush on the samples at 20 ml min ^-1 . Peak temperatures are reported as melting points.

Thermal Gravimetric Analysis (TGA)

TGA data was collected on a Mettler Toledo STARe System (TGA851e module and 9.20 version of STAR software) equipped with a 34-position self-sampler. Unless otherwise stated, approximately 5 mg of a sample is usually heated from 30 ° C. to 250 ° C. at 10 ° C. min ⁻¹ in an automatic piercing aluminum pan. Nitrogen flush was maintained on the samples at 10 mlmin ^-1 .

Reference example 1 1) Synthesis of 5-methoxy-2- (2H-1,2,3-triazol-2-yl) benzoic acid

2-iodo-5-methoxybenzoic acid (15.0 g; 53.9 mmol) was dissolved in anhydrous DMF (45 ml), and then 1H-1,2,3-triazole (7.452 g; 108 mmol) and cesium carbonate ( 35.155 g; 108 mmol). By adding cesium carbonate, the temperature of the reaction mixture was increased to 40 ° C, and gas was released from the reaction mixture. Copper (I) iodide (514 mg; 2.7 mmol) was added. This triggers a strong exothermic reaction, and the temperature of the reaction mixture reaches 70 ° C within a few seconds. Continue stirring for 30 minutes. Subsequently, DMF was evaporated under reduced pressure, after which water (170 ml) and EtOAc (90 ml) were added. The mixture was stirred vigorously and the pH was adjusted to 3-4 by adding citric acid monohydrate. The precipitate was filtered off, washed with water and EtOAc, and discarded. The filtrate was poured into a separating funnel and the phases were separated. The aqueous phase was extracted again with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and the solvent was evaporated to provide 7.1 g of 5-methoxy-2- (2H-1,2,3-triazol-2-yl) as a 94% pure white powder. Benzoic acid (6% impurity is regiospecific N1-linked triazolo derivative); t _R [min] = 0.60: [M + H] ⁺ = 220.21

2) Synthesis of (S) -1- (third butoxycarbonyl) -2-methylpyrrolidine-2-carboxylic acid

2-methyl-L-proline hydrochloride (99.7 g; 602 mmol) was dissolved in a 1/1 mixture (800 ml) of MeCN and water, and triethylamine (254 ml; 1810 mmol) was added. The temperature of the reaction mixture increased slightly. After cooling the reaction mixture to 10 ° C to 15 ° C, a solution of Boc ₂ O (145 g; 662 mmol) in MeCN (200 ml) was carefully added for 10 minutes. Stirring was continued at RT for 2 hours. MeCN was evaporated under reduced pressure, and an aqueous NaOH solution (2M; 250 ml) was added to the remaining aqueous portion of the reaction mixture. The aqueous layer was washed with Et ₂ O (2 × 300 ml), and then cooled to 0 ° C., after which the aqueous HCl solution (25%) was slowly and carefully added to adjust the pH to 2. A suspension formed during this procedure. The precipitate was filtered off and dried under HV to provide 110.9 g of the title compound as a beige powder; t _R [min] = 0.68; [M + H] ⁺ = 230.14

3) Synthesis of (S) -2-((2-amino-4-chloro-3-methylphenyl) carbamyl) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

(S) -1- (Third-butoxycarbonyl) -2-methylpyrrolidine-2-carboxylic acid (60 g; 262 mmol) and HATU (100 g; 264 mmol) were suspended in DCM (600 ml), and then DIPEA (84.6 g 654 mmol) and 6-chloro-2,3-diamine toluene (41 g; 262 mmol). The reaction mixture was stirred at rt for 14 hours, then concentrated under reduced pressure, and water was added to the residue, followed by EtOAc (3 times) The product was extracted. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated under reduced pressure to provide 185 g of the title compound as a dark brown oil, which was used in the next step without further purification; t _R [min] = 0.89; [M + H] ⁺ = 368.01

4) Synthesis of (S) -2- (5-chloro-4-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

(S) -2-((2-Amino-4-chloro-3-methylphenyl) aminomethyl) -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (185 g; 427 mmol) Dissolved in AcOH (100%; 611 ml), heated to 100 ° C and continued stirring for 90 minutes. AcOH was evaporated under reduced pressure, and the residue was dissolved in DCM, after which a saturated sodium bicarbonate solution was carefully added. The phases were separated, the aqueous phase was re-extracted with DCM, the combined aqueous phases were dried over MgSO ₄ , filtered and the solvent was evaporated under reduced pressure to provide 142.92 g of the title compound as a dark brown oil, which was used in the next step after further purification. ; T _R [min] = 0.69; [M + H] ⁺ = 350.04

5) Synthesis of (S) -5-chloro-4-methyl-2- (2-methylpyrrolidin-2-yl) -1H-benzo [d] imidazole hydrochloride

(S) -2- (5-Chloro-4-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-carboxylic acid tert-butyl ester (355.53 g; 1.02 mol) was dissolved in dioxane (750 ml), and then a solution of HCl in dioxane (4M; 750 ml; 3.05 mol) was carefully added. The reaction mixture was stirred for 3 hours, after which Et ₂ O (800 ml) was added, triggering precipitation of the product. The solid was filtered off and dried under high vacuum to provide 298.84 g of the title compound as a reddish powder; t _R [min] = 0.59; [M + H] ⁺ = 250.23

6) Synthesis of [(S) -2- (5-chloro-4-methyl-1H-benzimidazol-2-yl) -2-methyl-pyrrolidin-1-yl]-(5-methoxy -2- [1,2,3] triazol-2-yl-phenyl) -methanone

(S) -5-chloro-4-methyl-2- (2-methylpyrrolidin-2-yl) -1H-benzo [d] imidazole hydrochloride (62.8 g; 121 mmol) was dissolved in DCM ( 750 ml), and then 5-methoxy-2- (2H-1,2,3-triazol-2-yl) benzoic acid (62.8 g; 121 mmol) and DIPEA (103 ml; 603 mmol) were added. Stirring was continued for 10 minutes, after which HATU (47 g; 124 mmol) was added. The reaction mixture was stirred at RT for 16 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc (1000 ml) and washed with water (3 x 750 ml). The organic phase was dried with MgSO _4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by CC with EtOAc / hexane = 2/1 to provide 36.68 g of the title compound as an amorphous white powder. t _R [min] = 0.73; [M + H] ⁺ = 450.96

II. Preparation of Crystal Forms of Compounds Example 1: Preparation and Characterization of Compounds in Form 1 a) Preparation of inoculation material of the compound in crystal form 1

In a 7 mL vial, 0.2 g of the compound as an amorphous material was dissolved in 2 mL of MeOH. Leave the sample open in the environment and evaporate over the weekend. As observed under an orthogonal polarizer, an amorphous mass with some crystals was obtained. Add 0.05 mL of MeOH, close the vial and sonicate the sample for 1 minute and heat to 40 ° C. Repeating this procedure 3 to 4 times caused further crystallization, and after about 15 min the sample was further shaken at 25 ° C. for 1 h. The solid was then separated, dried under reduced pressure (2 mbar, room temperature) for 4 hours and allowed to equilibrate for 2 hours at room temperature and 58% relative humidity. An off-white powder was obtained as the compound in crystal form 1. This procedure may need to be repeated several times to obtain sufficient material for vaccination.

Alternatively, 0.4 mL of an ethanol / water mixture having a volume / volume ratio of 1/4 can be added to 0.1 g of the compound as an amorphous substance. The mixture was blocked for up to three days. Isolation, drying and equilibration as described above yield the compound in Form 1.

b) Preparation of compound in crystal form 1

2 g of the compound was mixed with 8 mL of an ethanol / water mixture having a volume / volume ratio of 1/4, and about 0.05 g of seed crystals were obtained using the procedure as described above. The samples were shaken overnight at room temperature, and the solids were separated, dried under reduced pressure (2 mbar, room temperature) for 4 hours and allowed to equilibrate for 2 hours at room temperature and 58% relative humidity. An off-white powder was obtained as the compound in crystal form 1.

Example 2: Preparation and Characterization of Compounds in Form 2

At room temperature, in a 4 mL glass, an electromagnetic stirrer was used to mix 0.05 mL of acetonitrile and 0.01 g of the compound in Form 1 for 3 days. The solid was isolated and dried under reduced pressure (30 min at 2 mbar), and the solid was a compound in crystalline form 2.

Alternatively, at room temperature, 0.1 mL of methyl-isobutyl ketone and 0.015 g of the compound in crystal form 1 were mixed in a 4 mL glass with an electromagnetic stirrer for 3 days. The solid was isolated and dried under reduced pressure (2 hours at 2 mbar) and the solid was a compound in the form of crystal 2.

III. Bioanalysis

To further characterize the biological activity of the compounds, the following procedures have been used to measure antagonist activity at the orexin receptor:

In vitro analysis: intracellular calcium measurement:

Chinese hamster ovary (CHO) cells expressing human orexin-1 receptor and human orexin-2 receptor were inactivated at 300 μg / ml G418, 100 U / ml penicillin, 100 μg / ml streptomycin, and 10% respectively. Fetal bovine serum (FCS) was grown in a medium (Ham F-12 with L-glutamic acid). Cells were seeded at 20,000 cells / well into 384-well black transparent bottom sterile plates (Greiner). The inoculation plates were incubated overnight at 37 ° C, 5% CO ₂ .

Human orexin-A as a agonist was prepared into a 1 mM stock solution in MeOH: water (1: 1) using 0.1% bovine serum albumin (BSA), NaHCO ₃ : 0.375 g / l, and 20 mM HEPES HBSS was diluted for analysis at a final concentration of 3 nM.

The antagonist was prepared as a 10 mM stock solution in DMSO, and then diluted in 384-well plates with DMSO. The diluted solution was then transferred to a solution containing 0.1% bovine serum albumin (BSA), NaHCO ₃ : 0.375 g / l, and 20 mM HEPES. HBSS. On the day of analysis, 50 μl of staining buffer (containing 1% FCS, 20 mM HEPES, NaHCO ₃ : 0.375 g / l, 5 mM probenecid (Sigma) in HBSS) and 3 μM fluorescent calcium indicator fluo-4AM (in DMSO A 1 mM stock solution containing 10% pluronic) was added to each well. Incubate 384-well cell plates in 5% CO ₂ at 37 ° C for 50 min, and then equilibrate at RT for 30 min before measurement.

Antagonists were added to the plate in a fluorescence imaging plate reader (FLIPR Tetra, Molecular Devices) at a volume of 10 μl / well, incubated for 120 min, and finally 10 μl / well agonist was added. Measure the fluorescence of each well at 1 second intervals so that the height of each fluorescence peak is comparable to the height of the fluorescence peak induced by orexin-A with a vehicle instead of an antagonist of approximately EC ₇₀ (for example, 5 nM). The IC ₅₀ value (the concentration of the compound required to inhibit 50% of the agonistic response) is measured and can be corrected using the IC ₅₀ value of the reference compound on the resulting plate. Optimized conditions are achieved by adjusting the rate of aspiration and the cell division protocol. The calculated IC ₅₀ value may fluctuate depending on the performance of daily cell analysis. Such fluctuations are known to those skilled in the art. The average IC ₅₀ values from several measurements are given as an average.

Compounds have been measured on orexin-1 receptors with IC ₅₀ values of 2 nM.

Compounds have been measured on orexin-2 receptors with IC ₅₀ values of 3 nM.

Measure brain and systemic concentrations after oral administration:

To assess brain penetration, compound concentrations were measured in plasma ([P]) and brain ([B]), 3 h after oral administration (e.g., 100 mg / kg) to male wistar rats (Or at different points in time). Compounds are formulated in, for example, 100% PEG 400. At the same time point (+/- 5 min), samples were collected on the same animal. Blood sampling from the caudal vena cava To a container with EDTA as an anticoagulant, and centrifuge to produce plasma. The brain was sampled after the heart was perfused with 10 mL of NaCl 0.9% and homogenized to a volume of cold phosphate buffered saline (pH 7.4). All samples were extracted with MeOH and analyzed by LC-MS / MS. The concentration is determined by means of a calibration curve.

Results obtained with the compound: 3h after oral administration (100 mg / kg, n = 3): [P] = 1280ng / ml; [B] = 1808ng / g.

Sedative effects: Alert EEG, EMG, and behavioral index recorded in vivo by biotelemetry in Vista rats.

Using the TL11M2-F20-EET miniature bio-telemetry implant (Data Science Int.) With two pairs of differential leads, telemetry electroencephalography (EEG) and electromyography (EMG) )signal.

Surgical implantation was performed under general anesthesia with Ketamin / Xylazin. A pair of differential EEG electrodes were used for the craniocerebral position and a pair of EMG wires were inserted on both sides of the neck muscle. After the operation, the rats were restored in a temperature-adjusted chamber and allowed to receive subcutaneous butylorphine analgesics twice a day for 2 days. They were then individually housed and allowed to recover for a minimum of 2 weeks. Thereafter, the rats in the feeding cages were placed in a ventilated noise reduction box and allowed to adapt to a 12-h light / 12-h dark cycle before continuous EEG / EMG recording began. The telemetry technology we use for this research allows accurate and stress-free acquisition of biological signals from rats placed in familiar cage environments, with no recording lead limiting their movement. The variables analyzed included insomnia and sleep at four different stages, spontaneous activity and temperature in the cage. Somnologica Science, a rodent scoring software that directly processes biochemical signals within 10s of the adjacent period, is used to assess the sleep and arousal stages. Scoring is based on the frequency assessment of EEG and the discrimination of amplitudes of EMG and autonomous activities. Using these measurements, the software determines the probability that all components in each period best represent active wake (AW), quiet wake (QW), no-REM sleep (NREM), or REM sleep (REM). Every 12h in light or darkness Calculate the percentage of total time spent in AW, QW, NREM sleep and REM sleep. The incubation period of the first significant NREM sleep and REM sleep episodes and the frequency and duration of their episodes were also calculated. Prior to administration of the test compounds, AW, QW, NREM sleep and REM sleep, cage activity and body temperature were measured on the basis of at least one total day and night cycle (12h night, 12h day). If the basal measurement indicates that the animal is stable, the test compound or vehicle is administered orally by gavage at the end of the 12-h daytime period at night, immediately before an increase in orexin and activity in the rat at night. Subsequently, all variables were recorded for 12 h after orexin receptor antagonist administration.

The compound has been tested in this analysis (oral dose: 30mg / kg orally; effect is analyzed over 6 hours): the result is: when compared to the vehicle control, the active arousal is -24%, and the cage activity is- 31%, NREM sleep was + 27%, and REM sleep was + 53%.

Claims (16)

A crystalline compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5- Methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, wherein the crystal form is characterized by the following peaks of refraction angle 2θ in the X-ray powder diffraction pattern : 8.6 °, 15.2 °, and 21.3 °; or the peaks of the following refraction angles 2θ exist in the X-ray powder diffraction pattern: 13.4 °, 18.3 °, and 24.0 °; where the X-ray powder diffraction pattern is made of Cu used in combination Kα1 and Kα2 radiation are obtained without Kα2 stripping; and the accuracy of these 2θ values is within the range of 2θ +/- 0.2 °. (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) in the crystalline form as in claim 1 (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, in which the following peak of refraction angle 2θ exists in the X-ray powder diffraction pattern: 8.6 °, 15.2 °, and 21.3 °; where the X-ray powder diffraction pattern is obtained by using a combination of Cu Kα1 and Kα2 radiation without Kα2 stripping; and the accuracy of these 2θ values is in the range of 2θ +/- 0.2 ° Inside. (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) in the crystalline form as in claim 1 (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, in which the following peak of refraction angle 2θ exists in the X-ray powder diffraction pattern: 8.6 °, 11.5 °, 13.4 °, 14.6 °, 15.2 °, 15.5 °, 19.3 °, 21.3 °, 22.4 °, and 26.4 °; where the X-ray powder diffraction pattern is radiated by the combination of Cu Kα1 and Kα2 without Kα2 Obtained by stripping; and the accuracy of these 2θ values is within the range of 2θ +/- 0.2 °. (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) in the crystalline form as in claim 2 (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, which basically shows an X-ray powder diffraction pattern as depicted in FIG. 2. (S)-(2- (6-Chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) in the crystalline form as in claim 3 (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, wherein the crystal form is hemihydrate. (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) in the crystalline form as in claim 5 (5-Methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, which can be obtained from: a) 2 g of (S)-( 2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1 , 2,3-triazol-2-yl) phenyl) methanone and 8 mL of ethanol / water mixture with a volume / volume ratio of 1/4; b) adding about 0.05 g of (S)-(2) in crystal form 1 -(6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1, Seeds of 2,3-triazol-2-yl) phenyl) methanone; c) shake at 300 rpm for about 16 hours at room temperature; d) filter and wash with 2 mL ethanol / water 1/4 (v / v) The cake was dried, and the product was dried at room temperature under reduced pressure of about 10 mbar (mbar) for 4 hours; and e) opened to equilibrium for 2 hours at room temperature and about 60% relative humidity. (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) in the crystalline form as in claim 1 (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, in which the following peak of refraction angle 2θ exists in the X-ray powder diffraction pattern: 13.4 °, 18.3 °, and 24.0 °; where the X-ray powder diffraction pattern is obtained by using a combination of Cu Kα1 and Kα2 radiation without Kα2 stripping; and the accuracy of these 2θ values is in the range of 2θ +/- 0.2 ° Inside. (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) in the crystalline form as in claim 1 (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, in which the following peak of refraction angle 2θ exists in the X-ray powder diffraction pattern: 10.9 °, 13.4 °, 14.3 °, 14.9 °, 18.3 °, 20.9 °, 21.1 °, 21.8 °, 24.0 °, and 30.1 °, where the X-ray powder diffraction pattern is radiated by the combination of Cu Kα1 and Kα2 without Kα2 Obtained by stripping; and the accuracy of these 2θ values is within the range of 2θ +/- 0.2. (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) in the crystalline form as in item 8 (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, which basically shows an X-ray powder diffraction pattern as depicted in FIG. 3. (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) in the crystalline form as in item 8 (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, wherein the crystal form is anhydrate. (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) in the crystalline form as in claim 10 (5-Methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, which can be obtained from: a) 10 mg of 0.05 in acetonitrile mixed in the form 1 ( S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone; b) stirred in a closed 4 mL vial for up to three days; c) separated; and dried under reduced pressure and room temperature for 2 hours . (S)-(2- (6-Chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrole in the form of any one of claims 1 to 11 Pyridin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, which is used in the preparation of pharmaceuticals. A pharmaceutical composition comprising, as an active ingredient, the compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d]) in a crystalline form as in any one of claims 1 to 11. Imidazol-2-yl) -2-methylpyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, and At least one pharmaceutically acceptable carrier. Compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methyl in crystalline form as in any of claims 1 to 11 Pyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone for use in the manufacture of a pharmaceutical composition, wherein the pharmaceutical combination The compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methylpyrrolidin-1-yl) as an active ingredient (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone, and at least one pharmaceutically acceptable carrier substance. Compound (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methyl in crystalline form as in any of claims 1 to 11 Pyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone for use in the treatment or prevention of a member selected from the group consisting of Disease or disorder: Sleep disorder, which is selected from the group consisting of dyssomnias, narcolepsy, sleep disorders related to general medical conditions, and substance-induced sleep disorders; anxiety disorders; and addiction. A crystalline form of (S)-(2- (6-chloro-7-methyl-1H-benzo [d] imidazol-2-yl) -2-methyl as in any of claims 1 to 11 Use of pyrrolidin-1-yl) (5-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) methanone for the preparation for treatment or prevention Agents for diseases or conditions consisting of sleep disorders, anxiety, addiction, cognitive dysfunction, mood disorders, and appetite disorders.